Researchers Behind the Journals

Author Profile: Jean-Charles Soria

New Clinical Cancer Research Deputy Editor

Jean-Charles Soria is a newly appointed Deputy Editor of Clinical Cancer Research and is currently a Senior Vice President and Head of the Oncology Innovative Medicines unit (iMED) at MedImmune, where he has overall responsibility for the global oncology portfolio with oversight of research, translational sciences, and clinical development in oncology. His work focuses on potential therapeutic treatments for cancer, especially in precision medicine and immuno-oncology. He has contributed to first-in-man trials of atezolizumab and pembrolizumab in lung cancer.

Dr. Soria has been a member of the AACR since 1998 and has regularly presented work at AACR Annual meetings since 1999. In 2001, Dr. Soria won the AACR-AFLAC Scholar in Training Award, which provides grants to promising young investigators.

He was a scientific committee co-chairperson of the 2014, 2015, and 2016 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposia and the 2015 AACR-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics. In 2016, he served as a co-chairperson for the AACR Annual Meeting Scientific Program Committee. In 2018, he became a Scientific Editor for Cancer Discovery.

Prior to his position at MedImmune, Dr. Soria was Head of the Drug Development Department (DITEP) at Gustave Roussy in Villejuif, France from 2013-2017. He was a Full Professor of Medicine and Medical Oncology at Paris-Sud Université XI from 2006-2017 and served as an Adjunct Professor of Medicine at the MD Anderson Cancer Center from 2013-2017. In 2018, the European Society for Medical Oncology awarded Dr. Soria the Targeted Anticancer Therapies award.

A selection of Dr. Soria’s recent articles from the AACR family of journals is provided below:

Author Profile: Chi Van Dang

Cancer Research’s New Editor-in-Chief

Chi Van Dang is the newly appointed Editor-in-Chief of Cancer Research and is currently the scientific director of the Ludwig Institute for Cancer Research, where he oversees the execution of Ludwig’s scientific strategy to advance the prevention, diagnosis, and treatment of cancer. He is also a professor at the Wistar Institute's Molecular and Cellular Oncogenesis Program. His work focuses on cancer cell metabolism, and his laboratory established the first mechanistic link between the MYC cancer gene and cellular energy metabolism.

An AACR member since 1996, Dang previously served on the editorial board of Cancer Research and Cancer Discovery, two of the AACR's most prestigious journals. He has held numerous committee posts at the AACR. He chaired the AACR's Clinical and Translational Cancer Research Grants Committee, served on the Science Education Committee and AACR Team Science Award Selection Committee, and served with distinction as a co-chair of the 2017 AACR Annual Meeting Program Committee.

Prior to joining the Ludwig Institute for Cancer Research and the Wistar Institute in 2017, Dr. Dang served as the director of the Abramson Cancer Center at the University of Pennsylvania and as the John H. Glick Professor of Medicine, a position he has held since 2011. Before moving to Philadelphia, Dr. Dang was the Johns Hopkins Family Professor in Oncology Research and vice dean for research at Johns Hopkins University School of Medicine. He directed the Hopkins Institute for Cell Engineering and was a professor of medicine, pathology, oncology, and cell biology, with joint appointments in molecular biology and genetics. Dang has a bachelor's degree in chemistry from the University of Michigan, a PhD in chemistry from Georgetown University, and a medical degree from Johns Hopkins University. He completed a fellowship at the University of California, San Francisco.

Dang was recently appointed to the National Cancer Institute (NCI) Blue Ribbon Panel that has informed the scientific direction and goals of Vice President Joe Biden’s National Cancer Moonshot Initiative. He is a member of the National Academy of Medicine, the American Academy of Arts and Sciences, the American Society for Clinical Investigation, and the Association of American Physicians, and is chair of the NCI’s Board of Scientific Advisors.

A selection of Dr. Dang’s recent research articles from the AACR family of journals is provided below:

Enhanced and deregulated expression of MYC oncogene drives the development of multiple tumors. This study expands knowledge of how MYC promotes tumorigenesis by establishing a significant role for MYC in the regulation of cell growth through expression of a long noncoding RNA, DANCR, that is widely overexpressed in human cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains mystifyingly difficult to treat, and outcomes are persistently poor, demanding the exploration of new therapeutic options. In this study, a clinically relevant and genetically characterized platform of human PDAC PDXs was used to explore the in vivo antitumor efficacy of cancer metabolism—targeted agents. Among the six metabolic inhibitors tested, phenformin was the most effective single agent across the PDXs. Efficacy of metformin, at a fivefold higher dose of phenformin, was less compared with phenformin. These results suggest that phenformin might represent a better biguanide to inhibit PDAC progression and provide the foundation for further evaluation of phenformin in pancreatic cancer.

Breast cancer, particularly triple-negative breast cancer, overexpresses c–MYC, which alters glutamine metabolism. This study shows that the dependency of breast cancer cells on glutamine can be effectively targeted by the transaminase inhibitor, aminooxyacetate (AOA). The cytotoxic effects of AOA were mediated largely through the stress response pathway. AOA also displayed antitumor effects in breast cancer animal models. This preclinical study provides a strong rationale for further clinical development of AOA, particularly for c–MYC—overexpressing breast cancers.

MYC regulates the transcription of several target genes, including metabolic enzymes, some of which drive aerobic glycolysis, a hallmark of cancer cells. This study reports that SLC16A1, the gene that encodes MCT1, is a MYC transcriptional target essential for lactate transport and glycolytic flux of certain cancer cell lines. MCT1 inhibition induced cell death through disruption of lactate export, glycolysis, and glutathione synthesis. Cotreatment with metformin augmented the in vivo efficacy of MCT1 inhibitors supporting the use of MCT1 inhibitors in combination with metformin in therapies for MCT1– and MYC–expressing malignancies.

The metabolic vulnerabilities of cancer have led to the development of novel therapies targeting diverse aspects of nutrient transport and utilization. This study indicates that monitoring aerobic glycolysis using 13C magnetic resonance spectroscopy with hyperpolarized pyruvate is a promising technique that could potentially detect the molecular effect of various emerging therapies targeting cell metabolism, and thus provide a radiation–free method to assess tumor response longitudinally.

Author Profile: F. Stephen Hodi

Accelerating Immuno-Oncology Innovation

F. Stephen Hodi, MD, is the Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber/Brigham and Women's Cancer Center and Professor of Medicine at Harvard Medical School. Dr. Hodi conducts clinical studies in immuno-oncology, which examines the ability of the immune system to detect and combat tumors. His primary research involves the clinical development of immune checkpoint inhibitors. This area of study includes the first-in-human clinical trials of ipilimumab, an anti–CTLA-4 monoclonal antibody, and the first long-term follow-up analysis of data from a phase I clinical trial testing an anti–PD-1 immunotherapy. A principal focus of Dr. Hodi’s current work lies in combinatorial treatment approaches, including combination of immune checkpoint blockade with cytokines as well as immune checkpoint blockade with antiangiogenesis.

Dr. Hodi is an active member of the American Association for Cancer Research (AACR), for which he is Chair of the 2015–2016 AACR–Ocular Melanoma Foundation Fellowship Scientific Review Committee and a member of the Cancer Immunology Working Group. He is also the Secretary/Treasurer for the Society for the Immunotherapy of Cancer; a founding member of the Society for Melanoma Research; and a member of the National Comprehensive Cancer Network, the ECOG-ACRIN Cancer Research Group Melanoma Committee, and the Alliance for Clinical Trials in Oncology Experimental Therapeutics Committee.

A selection of Dr. Hodi’s recent articles from the AACR family of journals is provided below:

This CCR Drug Updates article focuses on talimogene laherparepvec (T-VEC), a first-in-class oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an "in situ vaccine" effect. The authors analyze T-VEC’s clinical development, its use in current clinical practice for advanced melanoma, and current and future clinical development. They conclude that, in light of the increasing evidence that immune checkpoint blockade is mainly effective in patients with a preexisting T-cell–inflamed tumor microenvironment, T-VEC—along with other approaches that have the potential to mediate tumor-directed T-cell priming and trafficking into the tumor, such as vaccines—may become an increasingly important tool for cancer immunotherapy.

Pneumonitis has been recognized as a potentially life-threatening adverse event among patients with non–small cell lung cancer (NSCLC) who are treated with PD-1 inhibitors; however, the detailed clinical and radiographic manifestations of this entity remain to be described. The authors report on two cases of anti–PD-1 pneumonitis in patients with advanced NSCLC treated with nivolumab after its FDA approval, providing the first detailed description of the clinical and radiographic characteristics of PD-1 inhibitor–related pneumonitis in patients with NSCLC.

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non–small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes exerts similar effects. In this study, the authors investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Their findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1–mutated tumors with PD-1–targeting antibody therapies.

Inhibition of immune checkpoints, including CTLA-4 and PD-1, has brought durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. However, the activity of these agents for patients with glioblastoma is not known. The authors systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules administered as single agents and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. Their results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.

Author Profile: Jennifer R. Grandis

Head of the Class

Jennifer R. Grandis, MD, is a Professor at the University of California, San Francisco, in the Department of Otolaryngology—Head and Neck Surgery, and Associate Vice Chancellor—Clinical and Translational Research. As a trained physician, with specialties in surgery and infectious disease, she provides a unique understanding of the mechanisms that mediate head and neck (H&N) cancers.

As an investigator, her studies have been influential in defining the signal transduction pathways in the development and progression of head and neck squamous cell carcinoma (HNSCC). Her clinical expertise and emphasis on molecular characterization have been instrumental for the development of preclinical models of disease, predictive biomarkers, and novel therapeutic approaches, all of which have culminated into translational and clinical benefit for patients.

Dr. Grandis is a highly active member of the American Association for Cancer Research (AACR) and has previously served on the Board of Directors and in the capacity of course director, program chair, and member of many selection committees. On a number of occasions she has been invited to give lectures at national and international AACR meetings. She has contributed numerous peer-reviewed articles and currently serves as an Editorial Board Member or Scientific/Deputy Editor for many of the journals in the AACR family.

A selection of recent articles by Dr. Grandis and published in the AACR family of journals is provided below:

Detailed proteomic studies are invaluable for understanding the biology of cancer but are often overlooked. This article profiled a large cohort of patient-derived xenografts (PDXs) from HNSCC. Interestingly, while proteomic signatures were generally conserved between primary tumors and PDX models, important differences were revealed, providing new insight into the mechanisms that control tumor phenotypes.

A comprehensive genomic analysis was performed in this study, using a multitude of HNSCC cell lines and tumors to identify frequent amplification, deletion, and mutation events. Moreover, these data, combined with pharmacologic profiles of a number of therapies in multiple cell lines, suggest that gene mutations, in particular PIK3CA mutations, may guide preclinical model selection and aid in optimal therapeutic targeting.

This prospective article summarizes the key findings from recent genomic studies involving HPV-positive and -negative H&N cancers. In addition, it outlines the benefits of using targeted therapies for H&N cancers based on a better understanding of their genomics.

The VeraTag method was used in this study to characterize HER2, HER3, and HER2:HER3 heterodimer expression in HNSCC specimens from patients treated with targeted therapies. Findings indicate that agents targeting HER2 or HER3 hold promise for patients with HPV-positive HNSCC.

Targeted therapy in HNSCC has provided modest but favorable clinical responses, suggesting that personalized approaches will have utility in this tumor type. This review focuses on HER2 in HNSCC and discusses the rationale for its clinical investigation.

Author Profile: Steven A. Rosenberg

Cancer Immunotherapy Pioneer

Steven A. Rosenberg, MD, PhD, is Chief of Surgery at the National Cancer Institute and Professor of Surgery at the Uniformed Services University of Health Sciences and the George Washington University School of Medicine and Health Sciences. Immunotherapy continues to evolve, as evidenced by groundbreaking clinical trials documenting the power of immunotherapeutic approaches to treat cancer. Much of the framework for this research can be credited to Dr. Rosenberg, a pioneer in the development of effective immunotherapies and gene therapies for patients with advanced cancers. He introduced the first effective immunotherapy for human cancer, IL2, and demonstrated that the administration of IL2 can lead to durable complete responses in patients with metastatic melanoma and renal cancer.

Dr. Rosenberg’s studies have played a major role in positioning immunotherapy as a mainstream of cancer treatment. His current research aims to define the host immune response to cancer. These studies focus on the ability of human lymphocytes to recognize unique cancer antigens and the identification of antitumor T-cell receptors that can be exploited to develop new cell transfer immunotherapies.

Dr. Rosenberg is an active member of the American Association for Cancer Research (AACR), for which he is a Fellow of the AACR Academy. He has received numerous honors, including the American Cancer Society Medal of Honor (2015), the Partnership for Public Service’s Samuel J. Heyman Service to America Medal (2015), and the Cancer Research Institute’s William B. Coley Award for Distinguished Research in Tumor Immunology (2011).

A selection of Dr. Rosenberg’s recent articles from the AACR family of journals is provided below:

This commentary on the landmark article by Rosenberg and colleagues—which was published in the July 1, 2011, issue of Clinical Cancer Research—examines the power of the adoptive transfer of autologous antitumor T cells to mediate the complete, durable, and likely curative regression of cancer in patients with heavily pretreated metastatic melanoma.

In this article, the authors describe the discovery of a novel TCR for gene therapy that might circumvent toxicity to healthy tissue by targeting HPV-16 E6, a viral tumor antigen that is absent from healthy tissues. The authors demonstrate that gene-engineered T cells directed against HPV-16 E6 can recognize and kill cervical and head and neck cancer cells, and that they are unlikely to possess cross-reactivity against human proteins.

On the basis of the improved effectiveness of adoptive cell therapy using IL12 gene–modified cells in preclinical murine tumor models, the authors performed a first-in-human clinical trial evaluating therapy with IL12 gene–modified tumor-infiltrating lymphocytes (TIL). The administration of these TILs mediated cancer regression; however, the transferred cells did not persist long term and were associated with severe dose-limiting toxicity.

In this article, the authors show that pharmacologic inhibition of Akt results in enhanced persistence of TILs after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. These findings could form the basis for novel immunometabolomic approaches to improve cell-intrinsic features of therapeutic TILs that may enhance the clinical efficacy of cell-based immunotherapy for advanced cancer.

Author Profile: Keith T. Flaherty

Entering the Era of Combinatorial Therapy

Keith T. Flaherty, MD, holds the position of Associate Professor of Medicine at Harvard Medical School and Director of the Termeer Center for Targeted Therapy at the Massachusetts General Hospital Cancer Center, where he was recently named as the Richard Saltonstall Endowed Chair in Oncology. The goal of Dr. Flaherty's research is to understand the molecular and clinical consequences of inhibiting oncogenes and oncogenic pathways in melanoma, while establishing individual therapeutic approaches and constructing rational combinatorial therapies. A pioneer in developing targeted therapies matched to the genetic characteristics of a patient's tumor, Dr. Flaherty led early clinical trials on the development of vemurafenib and trametinib and the dabrafenib/trametinib combination.

Recent developments in targeted therapy and immunotherapy have revolutionized the treatment of melanoma; however, each of these approaches has limitations in overall response rates or duration of response. To improve the efficacy of both single-agent immune–targeted and signal-transduction–targeted therapy, Dr. Flaherty and other investigators have proposed combining these strategies, allowing for rational combinatorial regimens. Data from early efforts to build combinatorial regimens, as well as FDA drug approvals for melanoma, are discussed in the recently published CCR Drug Updates and CCR New Strategies articles written by Dr. Flaherty and his colleague Dr. Sullivan.

Dr. Flaherty is an active member of the American Association for Cancer Research (AACR), for which he serves as a Publications Committee member and a Clinical Cancer Research Senior Editor. He is also the Deputy Chair for Biomarker Sciences and the Chair of the Developmental Therapeutics Committee in the Eastern Cooperative Oncology Group, a Scientific Advisory Board member for the Melanoma International Foundation, and a Steering Committee member for the Society for Melanoma Research.

A selection of Dr. Flaherty's recent articles from the AACR family of journals is provided below:

This CCR Drug Updates article discusses pembrolizumab, the first anti–PD-1 monoclonal antibody approved by the FDA. The authors analyze the advantages and disadvantages of pembrolizumab over existing medications and conclude that while many issues remain regarding the ideal sequence and/or combination of this agent with other immune-targeted agents and/or molecularly targeted agents, pembrolizumab has made an enormous impact on the treatment of patients with advanced melanoma and represents an important therapeutic advance in this disease.

This review article focuses on new strategies in the treatment of metastatic melanoma. The authors describe the advances that have led to recent FDA approvals in melanoma, present emerging data from early efforts to build combinatorial regimens, offer insight into where the field is headed, and predict what the treatment landscape will look like in 5 to 10 years.

BRAFV600E is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcomes. In this study, the authors show that resistance to selective BRAF inhibitors can be mediated by the receptor tyrosine kinase EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance.

Two major advances in melanoma have occurred concurrently and involve treatment with targeted therapy and immune checkpoint blockade. However, each of these approaches has limitations with regard to overall response rates or duration of response. To address this, investigators have proposed combining these strategies, and this concept is being tested empirically in clinical trials. There is a scientific rationale supporting the combination of targeted therapy and immunotherapy, and these concepts are discussed in this review article.

The authors hypothesized that BRAF-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor immunity. To test this hypothesis, they developed a BRAF(V600E)/Pten–/– syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8+ T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8+ T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti–PD-1 or anti–PD-L1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth.

Author Profile: Frank McCormick

Paving the Way for Targeted Cancer Therapies

Frank McCormick, PhD, FRS, holds the title of Professor Emeritus at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center and the David A. Wood Chair of Tumor Biology and Cancer Research at UCSF. Dr. McCormick's research has focused on developing novel cancer therapies that counteract abnormal genetic changes, which activate oncogenic signaling pathways or eliminate tumor suppressors. Perhaps most notably, he initiated and oversaw drug-discovery efforts that led to the FDA approval of sorafenib for treatment of renal cell cancer and liver cancer.

In 2013, Dr. McCormick, a renowned expert in RAS biology, began working with the Frederick National Laboratory for Cancer Research, on behalf of the NCI, to lead the RAS Initiative. Although scientists have known for more than two decades that RAS mutations are present in several types of cancer, many still consider RAS proteins as virtually "undruggable" targets for therapy. To find new ways to approach the RAS enigma, the RAS Initiative established a hub of research activity focused on the study of cancer cells driven by RAS mutations and the development of therapies against RAS-driven cancers. As Guest Editor for the recently published CCR Focus, "Targeting RAS-Driven Cancers," Dr. McCormick, along with the other contributors, examines this tremendous unmet clinical need and renewed efforts to find therapies that target RAS proteins directly.

Dr. McCormick is an active member of the American Association for Cancer Research (AACR), for which he is a Fellow of the AACR Academy and Past President (2012). He has received numerous honors, including the American Society of Clinical Oncology's Science of Oncology Award and Lecture (2010) and the American Liver Foundation's Salute to Excellence Award (2008).

A selection of Dr. McCormick's recent articles from the AACR family of journals is provided below:

This review article focuses on KRAS, the major form of RAS that contributes to cancer. New technologies in drug discovery and insights into signaling pathways that KRAS controls have renewed efforts to develop therapies. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer hope that novel therapies for KRAS-mutant cancers are finally coming into view.

Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. In this article, the authors detail how they developed a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical–interrogation.

To advance RNAi therapy for KRAS-mutant cancer, the authors developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, the authors demonstrate that siRNA-mediated inhibition of KRAS, as well as RAF or PI3K combinations, can impair KRAS-mutant colorectal cancer in xenograft models.

RAF inhibitors such as vemurafenib activate the MAPK pathway and stimulate growth of RAS-mutated cells, possibly accounting for up to 60% of cutaneous squamous cell carcinomas or keratoacanthoma lesions with RAS mutations. To identify other contributing events, this study evaluated tumors from patients treated with vemurafenib for the presence of human papilloma virus (HPV) DNA. The results showed that HPV cooperates with vemurafenib to promote tumorigenesis in either the presence or absence of RAS mutations.

Author Profile: Roy S. Herbst

Advancing and Accelerating Personalized Cancer Medicine

Roy S. Herbst, MD, PhD, Ensign Professor of Medicine at Yale School of Medicine and Chief of Medical Oncology at the Yale Cancer Center, is nationally recognized for his expertise in lung cancer research and treatment. He is perhaps best known for his work in developmental therapeutics and personalized therapy for non–small cell lung cancer, specifically the process of linking genetic abnormalities of cancer cells to novel therapies. His current focus is on modernizing clinical trials to help accelerate the pace at which personalized cancer treatments are developed, tested, and approved. As coprincipal investigator of the recently published "Lung Master Protocol (Lung-MAP)," Dr. Herbst played an integral role in launching this unique biomarker-driven clinical trial that used state-of-the-art genomic profiling to match patients to substudies testing investigational treatments that may help target the genomic alterations driving the growth of their cancer.

Dr. Herbst is an active member of the American Association for Cancer Research (AACR), for which he serves as Vice-Chair of the Science Policy and Government Affairs Committee, Chair of the AACR Tobacco and Cancer Subcommittee, and a Senior Editor for Clinical Cancer Research. He is a member of the American Society of Clinical Oncology, the International Association for the Study of Lung Cancer, and SWOG. He is on the medical advisory board for the Lung Cancer Research Foundation and has received numerous honors, including the Bonnie J. Addario Lung Cancer Foundation's Excellence in Collaboration and Innovation Award (2014) and the Addario Lectureship Award (2014).

A selection of Dr. Herbst's recent articles from the AACR family of journals is provided below:

This review article offers an overview of some of the major discoveries in lung cancer. Recent developments have highlighted how lung cancer subtypes are molecularly distinct and have different therapeutic vulnerabilities. There also is an increasing appreciation for the fact that tumors evolve through treatment and that repeat biopsies at the time of disease progression can provide critical information to inform treatment strategies. These advances have the potential to significantly affect outcomes for patients with this disease in coming years.

This Perspectives in Drug Approval article presents an overview of the Lung Master Protocol (Lung-MAP, S1400), a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell lung cancer, for which there are currently no approved targeted therapies.

The studies detailed in this article establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Ra2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.

This article provides background on how the delineation of signaling pathways to understand tumor biology, combined with the development of technologies that allow broad molecular profiling, has led to a new era of personalized medicine. It highlights strategies on the horizon, including tests of RNA, protein, and immune parameters that are being developed and incorporated in clinical research.

Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. This review gives an overview of KRAS signaling pathways with an emphasis on novel targets and targeted therapies.

Author Profile: Harold F. Dvorak

Tumors: Wounds that do not heal—Redux

Harold Fisher Dvorak, MD, an investigative pathologist trained in immunopathology, was the recipient of the 2006 inaugural Albert Szent-Gyorgyi Prize for Progress in Cancer Research and the 2014 Canada Gairdner International Award for his discovery of vascular endothelial growth factor (VEGF), a protein that has been effectively targeted in cancer and wet macular degeneration.

In the early 1970s, Dr. Dvorak and colleagues demonstrated that delayed-type hypersensitivity reactions are heterogeneous, involving various immune-cell populations, and are associated with increased vascular permeability to plasma proteins due to the secretion by macrophages and mast cells of a new factor, which they characterized as the vascular permeability factor (VPF, renamed VEGF). These researchers were the first to demonstrate that tumor cells secreted VEGF, providing the molecular basis for the field of angiogenesis.

Dr. Dvorak's research has helped elucidate the nature and composition of tumor stroma and the pathogenesis of its generation. He made the critical observation that tumors behave like "wounds that do not heal" in that the vascular and stromal responses they induce closely mimic those of healing wounds. In both settings, and also in chronic inflammatory reactions, the initial sequence of events includes vascular hyperpermeability resulting in plasma fibrinogen extravasation, extravascular fibrin deposition, induction of angiogenesis, and progression to desmoplasia in tumors or to scar formation in wounds. VEGF is regarded as the key angiogenic factor contributing to the neovascularization associated with tumor growth and other adaptive or pathologic angiogenic responses. More recently, the Dvorak laboratory has characterized the different types of blood vessels that tumors generate and the molecular mechanisms by which they form.

A selection of Dr. Dvorak's recent papers from the AACR family of journals is provided below:

This Masters primer overviews the similarities between tumors and the inflammatory response associated with wound healing and chronic inflammatory diseases. Understanding how tumor cells usurp the wound-healing response to generate the stroma they need for survival and growth will lead to new therapeutic approaches to prevent and interfere with tumor growth.

Anti-VEGF therapies preferentially antagonize less mature blood vessels, with important implications for understanding the limited effectiveness of these therapies in human tumors where blood vessels that develop independently of tumor-secreted VEGF may predominate.

VEGF-A increases the expression and activation of pericyte cathepsin proteases and decreases that of a family of cysteine protease inhibitors, leading to the degradation of venular and capillary basement membranes. As pericytes detach, the formerly normal microvessels become fragile structures that are lined only by endothelium and are susceptible to microhemorrhages.

Author Profile: Arul M. Chinnaiyan

Furthering Diagnostics and Therapies in Cancer

The author profile feature gives the American Association for Cancer Research (AACR) a chance to highlight important work from the remarkable authors who publish in our journals and thereby foster our mission to prevent and cure cancer through research, education, communication, and collaboration. In this first author profile, we highlight the recent work of Aru M. Chinnaiyan, MD, PhD. As a board-certified pathologist, an endowed professor at the University of Michigan Medical School, the director of the Michigan Center for Translational Pathology, and a member of the Howard Hughes Medical Institute, Dr. Chinnaiyan has had an impact on diverse fields of cancer research and enabled collaborations across multiple disciplines. His notable contributions to oncology research include the discovery of the first fusion (TMPRSS2-ETS) in a common solid tumor and the development of the online gene profiling portal Oncomine as a bioinformatics resource platform, as well as his guidance of the next generation of translational researchers in his laboratory at the University of Michigan. His work has been recognized with several awards, including the inaugural AACR Team Science Award (2007) and the AACR Outstanding Achievement in Cancer Research Award (2008). The collaborative skills for which he has received this acclaim were exemplified once again when his multi-institutional research team focusing on precision therapy for advanced prostate cancer was selected for the Stand Up To Cancer—Prostate Cancer Foundation Dream Team. His service to the field on behalf of the AACR includes a term on AACR's board of directors (2011–2014), several invited presentations at AACR conferences, and his contributions as a scientific editor for Cancer Discovery. We are proud to note that a large amount of Dr. Chinnaiyan's research has been published in the AACR family of journals.

Please explore some of Arul M. Chinnaiyan's recent and important research contributions as a senior author in these publications from the AACR family of journals:

This Rapid Impact article from Molecular Cancer Research (MCR) identifies PCAT29 as the first AR-repressed lncRNA that functions as a tumor suppressor. The authors report that its loss may identify a subset of patients at higher risk for disease recurrence. MCR marks the first anniversary of its unique Rapid Impact feature with this article.

A long noncoding RNA known to be oncogenic is found to promote cell death during genotoxic stress, suggesting a novel clinical correlation between this little-understood class of RNAs and genotoxic cancer therapies.

Author Profile: Melody A. Swartz

Lymphatic vessels in cancer

Melody A. Swartz is a MacArthur Foundation Fellow and the William B. Ogden Professor at the newly founded Institute for Molecular Engineering at the University of Chicago. Dr. Swartz was trained in chemical engineering. Her PhD thesis work delineated the coupling of the transport functions of lymphatic vessels to the local tissue biomechanics and developed mathematical and experimental models to understand how the lymphatics respond to edema and restore homeostatic fluid balance. Her postdoctoral studies focused on airway biomechanics and how mechanical stresses are communicated between cells to instigate stress-dependent remodeling of the extracellular matrix. Her current work uses quantitative and multidisciplinary approaches to investigate the roles of the lymphatic system in immunophysiology and pathophysiology, focusing on the interface between vascular biology, transport biomechanics, and immunology. The investigators in her laboratory are exploring the function of lymphatic drainage in maintaining local immunologic tolerance, and the roles of lymphangiogenesis in inflammatory diseases, including cancer. Her team is applying the cumulative knowledge of systems immunology of the lymphatic system to develop novel immunotherapeutic approaches in cancer, including lymph node–targeting vaccine approaches.

A selection of Dr. Swartz's recent papers from the AACR family of journals is provided below:

This Masters of Immunology primer presents an overview of emerging evidence suggesting that lymphatic vessels and lymphangiogenesis play important immunomodulatory roles in host immunity and the tumor microenvironment.

This article shows in two models of cancer that targeting vaccines to the tumor-draining lymph node (tdLN) using nanoparticle carriers strengthens effector immunity and improves therapeutic outcomes compared with either nontargeted vaccines or targeted vaccines to the non-tdLN.

This article introduces a new mechanism of glioma invasion and helps explain why CXCL12–CXCR4 signaling and fluid flow pathways in the brain are each correlated with invasion and metastasis. These findings are important to enhance our understanding of brain cancer progression.